Beating arthritis together
Reproduced from Issue 125 of Arthritis Today
Prof Tim Spector
The UK Twin Register has helped to change the scientific establishment's ideas about the causes of common musculoskeletal conditions. Jane Tadman reports.
Ten years ago, the Arthritis Research Campaign played a major part in setting up the Twin Register. This month it earmarked another £100,000 to help medics maintain its thriving database. And in the years in between much has changed in the way that scientists regard common musculoskeletal diseases.
Professor Tim Spector, director of the twin research unit at St Thomas's Hospital in London, encapsulates this change succinctly: "For years the medical profession thought that osteoarthritis was to do with being fat, old or a footballer," he says. "What we did was to change that perception, and turn it on its head."
In early 1990's arc awarded Tim Spector, then at Barts Hospital, a project grant to investigate the possible role played by a person's genetic make-up in the development of osteoarthritis of the knee. Dr Spector and his team examined and x-rayed 250 pairs of twins. The results showed that identical twins were twice as likely to both have osteoarthritis in the hands and knees compared with non-identical twins. The researchers calculated that up to 65 per cent of osteoarthritis in the hands and knees was due to genetic factors – the first time that osteoarthritis had been shown to have a major genetic influence.
It was, and remains, a major breakthrough. "For fifty years osteoarthritis had been believed to be a wear and tear disease of ageing, and of little interest to research and clinicians," Dr Spector said at the time. "This should have a great impact on the direction of future research into this often forgotten disease."
This has been proven to be the case; more of that later. What the success of the project grant also led to was the establishment of the Twin Register, a massive data base of identical and non-identical twins, a goldmine of information that has proven vital in epidemiological and genetic studies.
"We had got these 500 twins, the knee OA project had gone so well, and no-one else was doing anything like it in this area, so we thought we would use the twins for other studies, and slowly this data base become the twins register," explains Tim Spector.
The register slowly expanded to its current size of 10,000 twins, and over the years they have contributed to the publication of numerous papers no longer just encompassing musculoskeletal conditions.
Prof Alex MacGregor
"Once it took on a life of its own the register spread to look at all diseases related to ageing, although in truth we have looked mostly at musculoskeletal disease, including bone conditions, cardiovascular diseases, and endocrine conditions such as diabetes," says Alex MacGregor, whose former arc fellowship led to extensive twin-based research.
"It's now the biggest twin register of its kind in the world, and the most detailed in terms of clinical information, and is a national and international resource for researchers with an interested in the genetics and epidemiology of musculoskeletal diseases."
So how can using twins establish that certain diseases have a strong genetic component? It's very simple – by comparing identical twins, who share all their genes, with non-identical twins, who are no more related than ordinary siblings, studies can separate the effects of shared genes from those in a shared environment.
After the strength of the genetic component in knee osteoarthritis was established, other studies followed. Dr Spector, Dr MacGregor and Dr Alan Hakim showed that genetic factors also played a major part in the development of osteoarthritis in the spine and hip, in disc disease and back pain, and in wrist fractures.
"We also provided the definitive evidence of an important genetic contribution underlying osteoporosis and Raynaud's phenomenon," says Alex MacGregor. "Our analysis has also identified genetically determined links between diseases such as Raynaud's, migraine and coronary vascular disease, that point to a common underlying genetic cause."
One of the unit's media-friendly studies was to find out the effects of moderate drinking on bone density in women. Fifteen hundred twins subjected their drinking habits to public scrutiny. The results revealed that contrary to expectations, that moderate drinkers may have a slightly stronger and higher bone mineral density than non-drinkers. The same data showed deleterious effects of smoking, indicating that alcohol is the lesser of the lesser of the two vices.
But perhaps the most surprising findings stem from the group's work on pain and soft tissue rheumatism. Studies of neck and back pain in the twins have shown that genetic factors have a dominating influence in the reporting of severe low back pain and neck pain in the population. In work carried out as part of his arc fellowship, Alan Hakim has also found that genes control the risk of developing soft tissue injuries such as tennis elbow, frozen shoulder and carpal tunnel syndrome.
"Several large studies have suggested that environmental triggers such as type of occupation are important causes of soft tissue damage," says Dr Hakim. "But in our study environmental triggers didn't explain all the liability of developing a disorder. For each of these conditions we found that genes account for up to half the risk. We also looked at joint hypermobility, so-called double-jointedness in the twins, and found that three-quarters of the risk of being hypermobile is genetic."
But other than undoubtedly changing people's perceptions about the origins of many common musculoskeletal disorders, how can knowing about genetic predisposition actually help people suffering from these conditions, or those who are likely to develop them in the future? Genetic testing has yet to happen and gene therapy – altering part of a person's genetic structure by replacing the faulty gene – is generally accepted to be many years down the research road.
Alex MacGregor concurs. "Just saying that a particular disease is 50 per cent genetic is not particularly meaningful, it's stating the blindingly obvious," he says. "We know genes and the environment cause disease. However, if you can show that in a population, not just in an individual, 50 or 60 per cent of a disease can be accounted for by genetic make-up, then that justifies major studies into gene linkage and looking to track down individual genes, like John Loughlin is doing in Oxford, for example. It puts some perspective into environmental effects, and it alters the way we think about disease.
"Knowing what we know sets researchers on the right track and opens up a whole range of risk factors for disease, Whether it can be translated into therapy or prevention is a much more difficult question."
So what's next for the twin register? arc is currently funding Alex MacGregor, now Professor of Epidemiology at the University of East Anglia, to investigate whether genetic factors influence pain perception, using data from 400 twins, and Tim Spector, Professor of Genetic Epidemiology, is using a group of more than 600 twins to find out if knock knees or other knee deformities which can lead to osteoarthritis, can be accounted for by genetic predisposition.
Cheers! Twins taking part in the study to investiage the effect of moderate drinking on bone density
The Wellcome Trust has given more than £1.5m to collect and bank DNA and urine samples from all 10,000 twins – a mammoth undertaking. And arc 's grant of almost £100,000 to run the musculoskeletal database for the next three years will enable designated staff to organise the register more effectively and make it accessible and more open to the wider research community as a repository for further studies.
"We're just starting to develop links with other international registers, including the European Twins Register, as genetic studies in the future will require very large population studies," says Alex MacGregor. "The data base set up is now bigger than the twins unit! The twin register could become a national treasure."
- Any twins who would like to volunteer to join the register can call the Twin Research Unit Hotline on 0207 188 5555 or go to www.twin-research.ac.uk
